Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. Editorial summary: Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morland et al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.

Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet (i.e. high fat diet: HFD) impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.

Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during calcium-overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance cognition by speeding action potential propagation and provide metabolic support to axons.

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE. Emphasis will be placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.

Stimulation of mitochondrial biogenesis during life-time challenges both eliminates disadvantageous properties and drives adaptive selection of advantageous phenotypic variations. Intermittent fission and fusion of mitochondria provide specific targets for health promotion by brief temporal stressors, interspersed with periods of recovery and biogenesis. For mitochondria, the mechanisms of selection, variability, and heritability, are complicated by interaction of two independent genomes, including the multiple copies of DNA in each mitochondrion, as well as the shared nuclear genome of each cell. The mechanisms of stress-induced fission, followed by recovery-induced fusion and biogenesis, drive the improvement of mitochondrial functions, not only as directed by genotypic variations, but also as enabled by phenotypic diversity. Selective adaptation may explain unresolved aspects of aging, including the health effects of exercise, hypoxic and poisonous preconditioning, and tissue-specific mitochondrial differences. We propose that intermittent purposeful enhancement of mitochondrial biogenesis by stressful episodes with subsequent recovery paradoxically promotes adaptive mitochondrial health and continued healthy aging.

Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKII-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder among children. ADHD children are hyperactive, impulsive and have problems with sustained attention. These cardinal features are also present in the best validated animal model of ADHD, the spontaneously hypertensive rat (SHR), which is derived from the Wistar Kyoto rat (WKY). Current theories of ADHD relate symptom development to factors that alter learning. N-methyl-d-aspartate receptor (NMDAR) dependent long term changes in synaptic efficacy in the mammalian CNS are thought to represent underlying cellular mechanisms for some forms of learning. We therefore hypothesized that synaptic abnormality in excitatory, glutamatergic synaptic transmission might contribute to the altered behavior in SHRs. We studied physiological and anatomical aspects of hippocampal CA3-to-CA1 synapses in age-matched SHR and WKY (controls). Electrophysiological analysis of these synapses showed reduced synaptic transmission (reduced field excitatory postsynaptic potential for a defined fiber volley size) in SHR, whereas short-term forms of synaptic plasticity, like paired-pulse facilitation, frequency facilitation, and delayed response enhancement were comparable in the two genotypes, and long-term potentiation (LTP) of synaptic transmission was of similar magnitude. However, LTP in SHR was significantly reduced (by 50%) by the NR2B specific blocker CP-101,606 (10 muM), whereas the blocker had no effect on LTP magnitude in the control rats. This indicates that the SHR has a functional predominance of NR2B, a feature characteristic of early developmental stages in these synapses. Quantitative immunofluorescence and electron microscopic postembedding immunogold cytochemistry of the three major NMDAR subunits (NR1, NR2A; and NR2B) in stratum radiatum spine synapses revealed no differences between SHR and WKY. The results indicate that functional impairments in glutamatergic synaptic transmission may be one of the underlying mechanisms leading to the abnormal behavior in SHR, and possibly in human ADHD

Eccentric muscle actions are associated with ultrastructural changes. The severity and types of change depend on the nature of the stimulation protocol, and on the method for assessing such changes, and can be regarded as a continuum from mild changes to pathological-like changes. Most studies describing more severe changes have been performed on animals and only a few in humans, some using electrical stimuli. Hence, a debate has emerged on whether voluntary actions are associated with the pathological-like end of the continuum. The aim of this study was to determine whether severe muscle damage, i.e., extensive ultrastructural changes, is confined to animal studies and studies on humans using electrical stimuli. Second, because there is no generally approved method to quantify the degree of muscle damage, we compared two published methods, analyzing the Z disks or sarcomeres, as well as novel analyses of pathological-like changes. A group of untrained subjects performed 70 voluntary maximal eccentric muscle actions using the elbow flexors. On the basis of large reductions in maximal force-generating capacity (on average, -62 +/- 3% immediately after exercise, and -35 +/- 6% 9 days later), five subjects were selected for further analysis. Biopsies were taken from m. biceps brachii in both the exercised and nonexercised arm. In exercised muscle, more disrupted (13 +/- 4 vs. 3 +/- 3%) and destroyed (15 +/- 6 vs. 0%) Z disks were found compared with nonexercised muscle. A significant proportion of exercised myofibers had focal (85 +/- 5 vs. 11 +/- 7%), moderate (65 +/- 7 vs. 11 +/- 6%), and extreme (38 +/- 9 vs. 0%) myofibrillar disruptions. Hypercontracted myofibrils, autophagic vacuoles, granular areas, central nuclei, and necrotic fiber segments were found to various degrees. The present study demonstrates that the more severe end of the continuum of ultrastructural changes occurs in humans after voluntary exercise when maximal eccentric muscle actions are involved

Physical exercise can improve brain function and delay neurodegeneration, but the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in fibroblast-like cells that line and surround the pial blood vessels supplying the brain, and that activation of HCAR1 stimulates vascular endothelial growth factor A (VEGFA) levels and angiogenesis in hippocampus. High intensity interval exercise (five days weekly for seven weeks), as well as L-lactate injected subcutaneously to similarly increase blood lactate levels, caused a substantial increase in brain VEGFA protein and microvessel density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle showed no vascular HCAR1 expression and no HCAR1 dependent change in vascularization induced by exercise or lactate. To our knowledge, this is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

While physical exercise is known to improve brain function and delay neurodegeneration, the signal from muscle to brain has not been identified. We show here that the lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1 also known as GPR81), mediates exercise induced increase in the content of vascular endothelial growth factor A (VEGFA) and in capillary density in the hippocampus and cerebral cortex. Mice were subjected to high intensity interval exercise 5 days per week for 7 weeks. Increases in VEGFA and capillary density were observed in wild-type (wt) mice, but not in knockout (ko) mice lacking HCAR1. Subcutaneous injections of L-lactate 5 days per week for 7 weeks, to achieve intermittently high blood lactate levels comparable to those after exercise, reproduced the findings in wt mice. No changes were observed in ko mice. The intermittent nature of the stimulation may be important since continuously high extracellular lactate has previously been observed to down-regulate HCAR1. To our knowledge, the present finding is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. No changes in VEGFA or capillary density were observed in the cerebellar cortex. HCAR1 was highly expressed in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in fibroblast-/pericyte-like cells along intracerebral microvessels. These cells are strategically placed to monitor changes in blood-born lactate as well as in brain extracellular lactate (which equilibrate across the vascular endothelium via monocarboxylate transporter 1). Skeletal muscle showed no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. As VEGFA governs neuronal functions such as LTP as well as vascular growth, the increases may have direct effects on neurons as well as indirect effects through enhancement of vascularization. Both disturbed vascularization and impaired synaptic function are components of the pathogenesis in neurodegenerative dementias such as Alzheimer’s disease. The lactate receptor HCAR1 may prove a useful nutraceutical target for intervention in persons at risk for dementia who are unable to exercise sufficiently to achieve optimal HCAR1 stimulation through rises in blood lactate.